Submissions for variant NM_000059.4(BRCA2):c.1247T>G (p.Ile416Ser)

dbSNP: rs80358418

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129196	SCV000183936	benign	Hereditary cancer-predisposing syndrome	2015-04-27	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV001284073	SCV000210557	likely benign	not provided	2019-01-09	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30254663, 16550498)
Color Diagnostics, LLC DBA Color Health	RCV000129196	SCV000906884	benign	Hereditary cancer-predisposing syndrome	2017-03-21	criteria provided, single submitter	clinical testing
Mendelics	RCV000077253	SCV001138993	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001112107	SCV001269728	uncertain significance	Fanconi anemia complementation group D1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV000077253	SCV001272998	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284073	SCV001469659	uncertain significance	not provided	2020-11-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001394892	SCV001596585	likely benign	Hereditary breast ovarian cancer syndrome	2025-01-20	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129196	SCV003849939	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
All of Us Research Program, National Institutes of Health	RCV000077253	SCV004846891	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700317	SCV005204540	uncertain significance	not specified	2024-06-20	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1247T>G (p.Ile416Ser, also described by its legacy name c.1475T>G in the literature ) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 249452 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1247T>G has been reported in the literature in individuals affected with breast and/or ovarian cancer without any strong evidence for causality (example: Bhai_2021, Santonocito_2020, Zuntini_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. A recent report from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge has classified this variant as neutral in a prediction protocol that includes assessment of the impact of this variant on splicing and protein function using four sets of predictors (Padilla_2019). Additionally, a co-segregation analysis also reports this variant to be likely not pathogenic (Zuntini_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34326862, 31294896, 31112341, 32438681, 16550498, 30254663). ClinVar contains an entry for this variant (Variation ID: 51091). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Sharing Clinical Reports Project (SCRP)	RCV000077253	SCV000109050	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-07-31	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077253	SCV000145840	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2001-10-29	no assertion criteria provided	clinical testing